TLR4-MEDIATED EPIGENETIC AND SENESCENCE MECHANISMS IN EMPHYSEMA

TLR4 介导的肺气肿表观遗传和衰老机制

基本信息

批准号：
9981929
负责人：
PATTY J LEE
金额：
$ 32.68万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981929
关键词：
Age Aging Alveolar Antioxidants CDKN2A gene Cause of Death Cell Survival Cells Cellular Structures Chronic Obstructive Airway Disease Chronic lung disease DNA DNA Modification Methylases DNA Modification Process DNMT3a Data Development Elderly Endothelial Cells Enzymes Epigenetic Process Epithelium Exhibits Experimental Models Future Gases Gene Expression Genes Genetic Genetic Transcription Goals HDAC2 gene Histones Human Immune Immune system Immunologic Receptors Impairment Infection Inflammatory Inhalation Injury Knock-in Mouse Knockout Mice Life Link Longevity Luciferases Lung Lung Capacity Lung diseases Maintenance Mediating Methylation Molecular Molecular Target Mus Natural Immunity Outcome Pathway interactions Post-Translational Protein Processing Predisposition Prevention Process Proteins Pulmonary Emphysema Recording of previous events Regulation Reporting Risk Factors Role Source Structure TLR4 gene Testing Tetanus Helper Peptide Therapeutic Toxic Environmental Substances Toxin adaptive immune response age related aged antimicrobial cell type cigarette smoke cigarette smoking clinically relevant design effective therapy exposed human population exposure to cigarette smoke histone deacetylase 2 in vivo inflammatory marker innovation insight mortality mouse toll-like receptor 4 new therapeutic target novel oxidant stress prevent response senescence stressor

项目摘要

PROJECT SUMMARY COPD is now the 3rd leading cause of death worldwide. Emphysema, characterized by airspace enlargement and impaired gas exchange, is a major subtype of COPD. The cumulative effects of cigarette smoke exposure (CS) and environmental toxins across the lifespan are important contributing factors to the development of emphysema. Yet very little is known about the underlying mechanisms, which limits therapies. Our overall goals are to understand the molecular mechanisms of how our lungs maintain normal structural integrity and how they protect against inhaled toxins, such as CS. We identified a critical role for an innate immune receptor, Toll-like receptor 4 (TLR4), in lung maintenance and in preventing inappropriate activation of aging and injury pathways. Unfortunately, age and CS, two of the most common risk factors for COPD, result in inadequate levels of TLR4, thus predisposing to emphysema. Our studies will fill current gaps in our understanding of how the immune system, in specific lung cells, can impact lung-protective responses even in the absence of infection, thereby offering potential new therapeutic targets. Using TLR4-deficiency and CS as clinically relevant experimental models of emphysema, we identified mechanistic roles for the senescence molecule, p16INK4A, and DNA-modifying enzymes, HDAC2, Dnmt3a and Tet2, in emphysema. In addition, we offer the first in vivo evidence that increased p16INK4A contributes to emphysema. Our overall hypothesis is that structural cell TLR4 is required to maintain normal lung integrity, at baseline and after CS, by inhibiting p16INK4A via HDAC2-Dnmt3a-Tet2-mediated mechanisms. We will use a combination of age- and CS- exposed human and mouse lungs/cells as well as innovative gene manipulations to test this hypothesis in the following Aims: 1) Identify mechanisms of decreased TLR4 expression with aging and CS and the contribution of TLR4 in specific structural cells to emphysema. 2) Determine the mechanisms of decreased HDAC2 in TLR4-deficient and CS-exposed cells. 3) Identify HDAC2 and Dnmt3a / Tet2 -mediated mechanisms of p16INK4A induction and the contribution of p16INK4A in specific structural cells to emphysema. Our studies will expand our basic understanding of the molecular drivers of emphysema, establish previously unrecognized interactions amongst innate immunity, senescence and DNA modifications and inform future preventative or therapeutic approaches to a range of age- and CS-related lung diseases.

项目概要慢性阻塞性肺病 (COPD) 目前是全球第三大死因。肺气肿，特点是空腔扩大和气体交换受损，是慢性阻塞性肺病的一个主要亚型。接触香烟烟雾的累积效应（CS）和整个生命周期的环境毒素是发育的重要影响因素气肿。然而，人们对潜在的机制知之甚少，这限制了治疗。我们的整体目标是了解我们的肺部如何维持正常结构完整性的分子机制以及它们如何防止吸入毒素，例如 CS。我们确定了先天免疫受体的关键作用， Toll 样受体 4 (TLR4)，用于肺维护和预防衰老和损伤的不当激活途径。不幸的是，年龄和慢性阻塞性肺病（COPD 的两个最常见的危险因素）会导致治疗不足 TLR4 水平升高，从而易患肺气肿。我们的研究将填补目前我们对如何即使在没有免疫系统的情况下，特定肺细胞中的免疫系统也可以影响肺保护反应感染，从而提供潜在的新治疗靶点。使用TLR4缺陷和CS作为临床肺气肿的相关实验模型，我们确定了衰老分子的机制作用，肺气肿中的 p16INK4A 和 DNA 修饰酶 HDAC2、Dnmt3a 和 Tet2。此外，我们还提供第一个体内证据表明 p16INK4A 增加会导致肺气肿。我们的总体假设是结构细胞 TLR4 是维持正常肺完整性所必需的，在基线时和 CS 后，通过抑制 p16INK4A 通过 HDAC2-Dnmt3a-Tet2 介导的机制。我们将结合使用年龄和 CS- 暴露的人类和小鼠肺/细胞以及创新的基因操作来检验这一假设以下目标：1) 确定 TLR4 表达随衰老和 CS 降低的机制以及特定结构细胞中 TLR4 对肺气肿的贡献。 2）确定减少的机制 TLR4 缺陷和 CS 暴露细胞中的 HDAC2。 3) 识别HDAC2和Dnmt3a/Tet2介导的机制 p16INK4A 诱导以及 p16INK4A 在特定结构细胞中对肺气肿的贡献。我们的研究将扩展我们对肺气肿分子驱动因素的基本了解，建立以前未被认识的先天免疫、衰老和 DNA 修饰之间的相互作用，并为未来的预防或预防提供信息一系列与年龄和 CS 相关的肺部疾病的治疗方法。